TDP-43 (TAR DNA-binding protein of 43 kDa) is known as a nuclear factor that binds to TAR (transactivation responsive region) DNA and that is involved in transcriptional modulation and alternative splicing.
In addition, TDP-43 is a protein that aggregates and accumulates in degenerated nerve cells such as those of frontotemporal lobar degeneration (FTLD) including frontotemporal dementia, in a form of a ubiquitin-positive intracellular inclusion (NCl), a degenerated spicular structure or the like (Arai T et al., Biochem Biophys Res Commun. 2006 Dec. 22; 351(3):602-11. Epub 2006 Oct. 30, Neumann M et al., Science. 2006 Oct. 6; 314(5796):130-3). Other than FTLD, TDP-43 is also known to accumulated in the nerve cells and glial cells of amyotrophic lateral sclerosis (ALS), Parkinson-dementia complex in Guam, Parkinson-dementia complex in Kii peninsula and the like. These diseases are collectively named as TDP-43 proteinopathies (TDP-43 protein storage diseases). Abnormal accumulation of TDP-43 is observed at the site of lesions of each disease which appears to imply close involvement in the cause of nerve degeneration in these diseases.
Presently, two types of commercially available antibodies are used for the studies on TDP-43 and the pathological diagnosis of TDP-43 proteinopathies. These antibodies, however, are known to bind not only to abnormally accumulated TDP-43 in the brain or spinal cord of a patient but also strongly to normal TDP-43 in the brain, spinal cord or the like, thereby rendering normal TDP-43 in the nuclear to be stained upon immunostaining of the brain or spinal cord specimens.
Meanwhile, although highly phosphorylated TDP-43 was found to accumulate in the brain or spinal cord of a patient (Arai T et al., Biochem Biophys Res Commun. 2006 Dec. 22; 351(3):602-11. Epub 2006 Oct. 30, Neumann M et al., Science. 2006 Oct. 6; 314(5796):130-3), there is no report as to the site of the phosphorylation or the enzyme involved in the phosphorylation.